Oxidized cellulose suture



Jan. 16, 1951 J. J. EBERL 2,537,979

OXIDIZED CELLULOSE SUTURE Filed NOV. 25, 1949 4 Sheets-Sheet 1 INVENTORLIZ/n55 cf 5524.

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Joah'ny in buffe 60/ INV NTOR Patented Jan. 16, 1951 2,537,979 OXIDIZEDCELLULOSE SUTURE James Joseph Eberl, Chester, Pa.,' assignor to EthicpnSuture Laboratories Incorporated, a corporation of New JerseyApplication November 25, 1949, Serial No. 129.413

1 This invention relates to absorbable sutures made from oxidizedcellulose threads.

Most absorbable sutures heretofore used have been of the catgut variety,although actually made from sheep intestines. These are nonhomogeneousboth as to strength and digestibility. due to diflerences in thestructure of the sheep's intestines from end to end, differences inindividual sheep, and seasonal variations. The best known manufacturingprocesses are uneconomicai because of the low yields that are obtainedand the high labor costs that are entailed.

These disadvantages are absent with oxidized cellulose sutures made inaccordance with the instant invention. The im roved sutures also possessmany advantages in their own right. For example, the digestion time ofan oxidized cellulose suture, i. e., the time required for the suture todisintegrate in human tissue may be fairly accurately controled byadiusting the de ree of oxidation. A sur eons knot made with an oxidizedcellulose suture has less tendency to slip than is the case with catgut.Such sutures are potentially less irritatin to the tissue since they donot behave like dead tissue in the human system. They are non-proteinousin nature and hence do not provide a culture medium for saprophyticorganisms. Their use thus reduces the chance of infection. Many otheradvantages inherent in the improved suture will be evident as thedescription of the invention proceeds.

It has been discovered in accordance with the invention that suturesmeeting U. S. Pharmacopoeia standards as regards tensile strength,

and strength over a sur eon's knot may be pre-' pared by oxidizingstrands of substantially pure ce lulose to different degrees dependingupon the ultimate rate of absorption the suture is to possess when inuse, provided the initial stren th and character of the cellulose threador strand is such that after the oxidation processes, sufilcientstrength remains in the various categories to satisfy suturerequirements.

According to U. S. Pharmacopoeia standards, catgut sutures of goodquality possess a dry tensile strength in the neighborhood of 2 gramsper denier. Knot strength requirements range from 1.0 to 1.4 grams perdenier. the lower value relating to the smaller sizes of catgut (Nos.00000 and 0000) and the higher value to the larger sizes.

Absorption time for catgut, i. e., the period required for digestion inthe human system, does not carry a U. S. P. designation. Catgut ismerely classified as Type A Plain, Type C Medium Chromic and Type DExtra Chromic. Type C.

z under ordinary conditions in the striate muscle, retains its integrityfrom to days and Type A and Type D a shorter and a longer period oftime, respectively. However, the absorption rate of catgut depends tosome extent upon the condition of the patient, absorption being mostrapid in a healthy man and slowest in young, aged, tubercular and anemicpatients. In mucous membranes, the digestion rate is about four times asfast as in muscular tissue.

Oxidized cellulose sutures may be made in accordance with the inventionhaving rates of digestion fully equivalent to catgut. Actually thedigestion rate of the improved sutures may be forecast with greateraccuracy than is possible for catgut since that of the former, at leastto the point of zero strength, depends upon the, pH of the body tissuewhereas that of the latter depends solely on enzymatic attack. The pH issubstantially constant from person to person and is also more constantthroughout the body than is gen dioxide.

enzyme distribution.

The improved sutures are oxidized with nitro- The oxidizing action isselective to produce oxidized cellulose threads of definite andpredictable characteristics and which will disintegrate by hydrolysis atthe pH of body tissue. When cellulose is oxidized by nitrogen dioxide orits dimer, the primary alcohol is converted to a carboxyl groupaccording to the following formula: i

t n t 3/ 110-04 o 110m o +Nolb t t l 1 According to an article by E. C.Yaekel and W. L. Kenyon, vol. 64 (1942) of the Journal of the AmericanChemical Society at page 121, in which the N02 oxidation is fullydescribed, complete theoretical oxidation with nitrogen dioxide resultsin a carboxyl content of approximately 25%. The instant inventioncontemplates a partial oxidation with nitrogen dioxide which throughoutthe specification is defined in percentage on the basis of completeoxidation as oxidation. In other words, 50% oxidation corresponds to acarboxyl content of approxi-. mately 12.5%.

In the accompanying drawings; Fig. 1 is a diagrammatic illustration ofappatime.

ratus in which cellulose thread may be oxidized b nitrogen dioxide.

Fig. 1A is a transverse section on line I-A-I-A through the oxidizingchamber of the apparatus shown in Fig. 1.

Fi 2 is a curve showing the per cent oxidation of cellulose fordiilerent nitrogen dioxide cellulose ratios.

Fig. 3 are curves showing the wet tensile strength of cellulose sutures,oxidized to different degrees with nitrogen dioxide, after soaking in abuffer solution of pH 7.5 for various periods of Fig. 4 is a curveshowing the time in days required for sutures oxidized to differentpercentages to go to zero strength after soaking in a buffer solution ofpH 7.5.

This application is a continuation-in-part of application Serial No.577,309, which became abandoned after the filing of the presentapplication.

In preparing oxycellulose sutures in accordance with the invention it isnecessary to sart with cellulose threads of high initial tensilestrength. Exact figures cannot be given because the required strengthwill vary depending upon the kind of cellulose thread used and itsconstruction. However, since the oxidation of cellulose thread lowersits strength, it is necessary that the initial strength be high enoughto enable the thread to undergo the oxidation process and still producea usable suture.

The process of oxidizing cellulose threads by nitrogen dioxide may besubstantially similar to that used by E. C. Yackel and W. L. Kenyon anddescribed in their article previously referred to. Suitable apparatus isdisclosed in Fig. l and includes, in part, a reaction chamber I which isclosed at the bottom and a measuring chamber 2. These chambers areconnected together at the top by a tube 3 which includes a pair of stopcocks l and 5 with an intermediate connecting seal 6. The measuringchamber is similarl connected by a tube I with achamber 8 constituting areservoir for a supply of liquid nitrogen dioxide. The tube I alsocontains a pair of stop cocks 9 and I0 and an intermediate connection 6.The apparatus shown may be glass, although commercial runs may be madein apparatus otherwise designed.

The thread to be oxidized is located in the reaction chamber I where itis supported by any suitable means as by protrusions I3 upset inwardlyfrom the walls thereof (Fig. l-A) above the level assumed by the liquidN02 which is later introduced. To prevent the formation of nitric acidwhich, in a gaseous oxidation, has a deleterious sheet on the strengthof the oxidized threads, all moisture is exhausted from the reactionchamber with the aid of a vacuum pump. This may be done before the seal6 is made. It may also be desirable to place a suitable amount ofphosphorous pentoxide in both the chambers I and 8 to absorb any waterthat finds its way into the nitrogen dioxide.

An amount of pure liquid nitrogen dioxide (boiling point 21 C.) necessarto oxidize a cellulose thread the desired amount is then introduced intothe reaction chamber I. This is accomplished by closing the stop cock 5,opening the stop cocks 9 and I0 and distilling a measured amount ofnitrogen dioxide from the chamber 8 into the measuring tube 2, the lowerend of which may be located in a container II of ice and rock salts. Thestop cocks 9 and I0 are then closed.

and the stop cocks t and 5 opened and the measured amount of nitrogendioxide distilled into the reaction chamber I which likewise may beimmersed at its lower end in a container I2 of ice and rock salts. Afterthe measured quantity of nitrogen dioxide has been completelytransferred to the reaction chamber, the stop cock 4 is closed and thecontainer I2 removed to allow the nitrogen dioxide to assume its gaseousform. The reaction is allowed to proceed for a period (say 64 hours)which is suflicient to insure the maximum oxidizing effect for theamount of nitrogen dioxide used.

The amount or weight of nitrogen dioxide used will depend upon theweight of the cellulose thread undergoing oxidation and the percentageof oxidation desired. The relationship between per cent oxidation ofcellulose and the nitrogen dioxide-cellulose ratio is shown in Fig. 2.The data for this curve may be found in the Yackel and Kenyon article.

At the end of the reaction time, the seal 6 is broken and the chamber Iplaced on a vacuum line for about two hours. The oxycellulose threadsare then removed. thoroughly washed with distilled water to remove suchnitric and nitrous acid as may have formed, and then dried.

Example I 7.55 grams of cotton thread, comprising a single strand wereplaced in reaction chamber I. All moisture was exhausted from thereaction chamber by means of a vacuum pump, stop cock II) being closed.A chamber 8 containing liquid N02 over P205 was sealed by aglass-to-glass seal to the section of the apparatus containing thereaction chamber. 3.4 grams of pure liquid N02 was introduced intoreaction chamber I. This was accomplished by closing stop cock 5,opening stop cocks 9 and I0, and distilling the N02 from chamber 8 intomeasuring tube 2, the lower end of which measuring tube was located in acontainer II holding an ice bath. Stop cocks 9 and I0 were then closedand stop cocks 4 and 5 were opened. The N02 in tube 2 was then distilledinto reaction chamber I which was immersed at its lower end in containerI2 containing an ice bath. Stop cock 4 was then closed and container [2was removed from proximity with chamber I, whereupon the N02 in chamberI changed from the liquid to the gaseous phase. The oxidation reactionwas allowed to proceed for a period of about 64 hours. At the end of thereaction time seal 6 was broken and a vacuum line was attached to thetop adiacent to stop cock III at the point where the seal was broken,and a vacuum was applied for a period of 2 hours, The thread was thenremoved, thorough washed with distil ed water. and dried. An ana ysis ofth thread showed that it was oxidized to the extent of 46.8%. Thethreads were placed in a solution buffered at a pH of 7.5. A weight of398 rams (1.2 grams/denier) was reouired to break the wet strand after 5m nutes immersion in the so ution buffered at a H of 7.5. A weight of141 rams (0.48 grams/denier) was required to break th wet strand after24 hours immersion in the buffer solution. A wei ht of 59 grams (0.17gram/denier) was required to break the strand aft r immersion in thebuffer solution for 48 hours. The strand had gone to zero stren th aft r'79. h rs imm sion in the buffer sol tion and it reouired no measurablewei ht to break th wet strand after immersion in the butler solutionafter 72 hours.

I Example II This experiment was conducted in the same manner as ExampleI except that the thread used weighed 7.45 grams, and the weight of N01introduced into reaction chamber l was 3.3 grams. The washed and driedstrand after removal from the reaction chamber showed on analysis thatit had been oxidized to the extent of 36.7%. The thread was placed in asolution builered at a pH of 7.5. A weight of 314 grams (0.99grams/denier) was required to break the wet strand after 5 minutesimmersion in the solution buffered at a pH of 7.5. The wet strandrequireda 159 gram weight (0.50 grams/denier) to break it after havingbeen immersed for 24 hours in the buffer solution. Eighty-nine grams(0.28 grams/denier) were required to break a wet strand after immersionfor 48 hours in buffer solution; 27 grams (0.84 grams/denier) wererequired to break the wet strand after immersion for 120 hours in thebuffer solution.

In the following table there is given, by way of example, thecharacteristic features of oxidized cellulose sutures prepared byoxidizing Egyptian cotton thread with nitrogen dioxide:

thread with 27% oxidation goes to zero strength after about 11 days anda thread with 53% oxidation goes to zero strength in about 1 day.Threads of greater and lesser percentage oxida- 5 tion lose strength inshorter and longerperiods of time respectively. Within the range of from27% to 53% oxidation there is a decrease in the time required for anoxidized thread to go to zero strength which is substantially linearlyprom portional to oxidation increase; for each 2.6% increase inoxidation, the time required to go to zero strength is one day less.This linear relationship is graphically shown in Figure 4.

By interpolation, one skilled in the art will be 15 able to select theproper degree of oxidation necessary to produce a suture which willdigest to zero strength at body conditions in any desired period oftime. The curve in the drawing of Figure 3 which represents 42.6%oxidation. is obtained by interpolation and no actual oxidation to 42.6%of the theoretical with nitrogen dioxide was made. Clinical testsconfirm the results obtained under laboratory conditions. It might beadded here that only rarely would it be desirable 5 to prepare a suturehaving a digestion rate of less than five days. This invention isdirected to TABLE Dry strength Wet strength Strength Diameter Denierbefore Oxidation $53 323; g gs fig;

treatment oxidation oxidation Inches GJdmicr Per cent GJdmier GJdmier0058 310 3.8 15 1. 5 I. l 0058 306 3. 8 l5 1. 8 l. 4 0060 314 3. 8 27 1.8 1. 6 0057 320 3. 8 27 1. 7 l. 5 0060 356 3. 8 38 1. 8 1. 3 0070 3913.8 48 1. 7 1. l 0070 405 3. 8 53 1. 8 1. 2 0078 441 3. 8 61 1. 4 0. 8

It will be observed from the foregoing table that cellulose threadoxidized with nitrogen dioxide up to about 55% will produce good suturematerial as far as strength is concerned. Wet strength which actually isthe most important factor is greater than it is for catgut. The drystrength is somewhat less than the U. S. Pharmacopoeia requirements forcatgut, although still adequate for suture material. Knot strength isadequate in all instances where the thread otherwise satisfies suturerequirements. It might be mentioned that all figures given in the tablerepresent an average of 10 readings.

The absorbability of oxidized cellulose sutures, i. e., the length oftime they retain their integrity in use-depends upon their degree ofoxidation. Within the range of oxidation that produces acceptablesutures as regards strength, a range of oxidation may be selected thatwill result in a suture having a rate of digestion equivalent to catgut.The rate of digestibility of oxidized cellulose sutures may be obtainedby soaking the sutures in a solution which simulates body conditions as,for instance, a phosphate solution buffered to pH 7.5 (pH of tissue) andmaintained at a temperature of 37 C. Such a solution may be prepared asfollows:

1000 cc. Na2HPO4 121-120 containing 23.88 g./liter 178.3 cc. KH2PO4containing 9.078 g./liter The oxidized cellulose threads of tests 2, 4,and 7 of the table and of Examples I and II were soaked in the abovesolution and the results plotted in Figure 3. The results indicate thata the provision of oxidized cellulose suture strands which will go tozero strength at the pH of body tissue (7.3-7.5) in a period of at least5 days. The standards for tensile strength of catgut sutures as given inthe U. S. Pharmacopoeia are arbitrary and not necessarily applicable tosutures of the type comprehended herein. The dry tensile strengths ofthe improved sutures are, in many instances, superior to catgut. But,even when dry strength is inferior, wet strengthwhich actually is themost important factor-is oftentimes superior to catgut. Because of themany factors involved. it is quite impossible to arbitrarily place anumerical value on the lower limit of tensile strength the treatedsuture should possess. Any cellulose thread, treated in the mannerdescribed and which is strong enough to perform the function of a sutureis within the scope of the invention. In the claims, therefore,

this strength factor has been termed suture tenacity.

It is also relatively difiicult to fix quantitatively the maximum degreeof oxidation for the cellu- 05 lose thread. Therefore, in the claims,this has been defined as that which will cause the thread to proceed tozero strength at the pH of body tissue in not less than the period oftime required for normal healing of a sutured wound, i. e., five days.

The invention has been described in its preferred embodiments but manymodifications thereof are included within its spirit. It is to belimited, therefore, only by the scope of the To appended claims.

What is claimed is:

1. A thread of suture tenacity comprising cellulose oxidized selectivelywith nitrogen dioxide by converting primary alcohol groups to carboxylgroups to an extent not greater than 42.6% of the theoretical oxidationwith nitrogen dioxide, oxidation to this extent beingsuflicient to causereduction of the thread to zero strength at the pH of body tissue(7.3-7.5) in a period of at least five days.

2. A thread of suture tenacity comprising cellulose oxidized selectivelywith nitrogen dioxide by converting primary alcohol groups to carboxylgroups to an extent within the range of from 42.6% to 27% of thetheoretical oxidation with nitrogen dioxide, oxidation to this extentbeing sufiicient to cause reduction of the thread to zero strength atthe pH of body tissue (7.3-7.5) in a period of at least five days but ina, period substantially not greater than eleven days.

JAMES JOSEPH EBERL.

REFERENCES CITED The following references are of record in the file ofthis patent:

UNITED STATES PATENTS Number Name Date 861,231 Clark July 23, 19072,092,512 Herrmann et a1 Sept. 7, 1937 2,232,990 Yackel et a1. Feb. 25,1941 FOREIGN PATENTS Number Country Date 195,090 Germany Feb. 19, 1900OTHER REFERENCES Pages 1138 and 1139, volume III of Worden, Technologyof Cellulose Ethers, published 1933 by Worden Laboratory and Library,Millburn, New Jersey. The volume cited is found in Div. 6 of the U. S.Patent Office.

Page 1668, Worden, Technology oi? Cellulose Esters, volume I, Part 3,published 1921 by Worden Laboratory and Library, Millburn, N. J. Thevolume cited is available in the Scientific Library of the U. S. PatentOfiice.

Pages 567 to 5'70 01 McLeod, Physiology in Modern Medicine, 8th edition,published in 1938 by the C. V. Mosby Company, St. Louis, Missouri. Acopy is available in Div. of the U. S. Patent Ofiice.

1. A THREAD OF SUTURE TENACITY COMPRISING CELLULOSE OXIDIZED SELECTIVELYWITH NITROGEN DIOXIDE BY CONVERTING PRIMARY ALCOHOL GROUPS TO CARBOXYLGROUPS TO AN EXTENT NOT GREATER THAN 42.6% OF THE THEORETICAL OXIDATIONWITH NITROGEN DIOXIDE, OXIDATION TO THIS EXTENT BEING SUFFICIENT TOCAUSE REDUCTION OF THE THREAD TO ZERO STRENGTH AT THE PH OF BODY TISSUE(7.3-7.5) IN A PERIOD OF AT LEAST FIVE DAYS.